Osteoporosis (OP) is a common clinical phenomenon in patients with knee osteoarthritis (KOA), but there lacks an unified homotherapy for heteropathy of OP and KOA.

To explore the multi-dimensional relationship of "traditional Chinese medicine (TCM) syndrome type- clinical feature-molecular typing" in patients with postmenopausal KOA, thus providing references for homotherapy for heteropathy of OP and KOA.

A total of 300 patients with postmenopausal KOA and treated with knee replacement surgery at the Joint Center of the Third Affiliated Hospital of Guangzhou University of Chinese Medicine from 2021 to 2023 were retrospectively included. According to the results of bone density measurement (BMD), patients were divided into three groups: normal bone density group, osteopenia group, and osteoporosis group, with 100 patients in each group. The correlation between the TCM syndrome type and BMD was analyzed in postmenopausal KOA patients by a correspondence analysis. The clinical symptoms [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score], laboratory indicators [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum calcium, phosphorus, alkaline phosphatase (ALP), and lipids)], and imaging indicators [Kellgren-Lawrence (K-L) grade, hip knee ankle angle (HKA), joint line convergence angle (JLCA), tibial plateau subchondral area, and low-density area] were investigated and compared among postmenopausal KOA patients with different TCM syndrome types. The knee joint tissues of KOA patients with different TCM syndrome types were analyzed by molecular biology, and the key target molecules were clarified. Subsequently, the key targets obtained by bioinformatics were detected by Western Blotting and immunohistochemistry experiments, and their expression differences were compared. An initial molecular classification of TCM syndrome types was established in patients with postmenopausal KOA.

The main TCM syndrome types in postmenopausal women with KOA included the liver and kidney deficiency (n=122), Qi stagnation and blood stasis (n=96), cold and damp obstruction (n=72), and phlegm and blood stasis (n=10). Qi stagnation and blood stasis was the major TCM syndrome type in postmenopausal KOA patients with a normal BMD, while the liver and kidney deficiency dominant in those with decreased bone density and osteoporosis. There was a significant difference in the distribution of TCM syndrome times among the three groups (χ2=55.27, P<0.001). Logistic regression analysis showed that patients with the TCM syndrome of liver and kidney deficiency had a significantly higher risk of decreased bone density (OR=2.37, 95%CI=1.20-4.69, P=0.013) and osteoporosis (OR=3.39, 95%CI=2.41-4.76, P<0.001). Patients with the TCM syndrome of liver and kidney deficiency had significantly higher WOMAC body function scores and total WOMAC scores than those with Qi stagnation and blood stasis (P<0.05). There were no significant differences in ESR, CRP, total calcium, phosphorus, ALP, and four blood lipids between patients with the TCM syndrome types of liver and kidney deficiency, and Qi stagnation and blood stasis (P>0.05). The HKA was significantly smaller in patients with the TCM syndrome of liver and kidney deficiency than those with Qi stagnation and blood stasis, and the JLCA and tibial plateau subcutaneous low-density area were significantly larger (P<0.05). There was no significant difference in the area of the tibial plateau between the two TCM types of patients (P> 0.05). There was a significant difference in K-L grade between the TCM syndrome types of liver and kidney deficiency and Qi stagnation and blood stasis (P<0.05), with the former being R- significantly greater than the latter (P<0.05). Western Blotting and immunohistochemistry experiments showed that the expression levels of C-X-C chemokine ligand 8, tumor necrosis factor-alpha and interleukin-1beta molecules were significantly higher in patients with the TCM syndrome type of Qi stagnation and blood stasis, while the expression levels of peroxisome proliferator-activated receptor gamma, stearoyl-CoA desaturase and CCAAT/enhancer-binding protein alpha molecules were significantly higher in patients with the TCM syndrome type of liver and kidney deficiency (P<0.05).

The multidimensional relationships between "TCM syndrome type-clinical features-molecular typing" in postmenopausal KOA patients are as follows: patients with Qi stagnation and blood stasis have normal bone mass and increased expressions of inflammation-related molecules, and those with liver and kidney deficiency have decreased/osteoporotic bone mass and increased expressions of lipid metabolism-related molecules. Compared with Qi stagnation and blood stasis, patients with liver and kidney deficiency have a higher risk of decreased bone mass, osteoporosis, and lower limb inversion deformity. Their tibial plateau subchondral low-density area is significantly larger, knee function is significantly impaired, and the K-L grade is more severe.